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Subjects

Abstract

The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the TH1 and TH17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution S12N (CARD9S12N), is associated with several autoimmune diseases. However, the function of CARD9S12N has remained unknown. Here we generated CARD9S12N knock-in mice and found that CARD9S12N facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9S12N mediated CLR-induced activation of the non-canonical transcription factor NF-κB subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive TH2 cell–mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9S12N can turn alveolar macrophages into IL-5-producing cells and facilitates TH2 cell–mediated pathologic responses.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (31622023 and 81571611 to X.M.J, 81630058 and 91542107 to X.L.), Outstanding academic leader program of Shanghai health and Family Planning Commission (2017BR024 to X.M.J.),Shanghai laboratory animal research fund (16140902600 to X.M.J), Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (17SG24 to X.M.J.),a start-up fund from the Tsinghua University-Peking University Joint Center for Life Sciences (with grants from Tsinghua University to X.L.) and Shanghai Leading Talent Program (2016036 to J.F.X).

(a) Gating strategy for flow assay of Th2 (CD3+CD4+ICOS+ST2+) cell recruitment in the lungs of WT and CARD9S12N KI mice at day 6 after single intratracheal exposure to Af conidia (1×107). (b) Gating strategy for flow assay of T-bet and GATA3 proteins in CD3+CD4+T cells from the lungs of the above disposed mice. (c) Gating strategy for flow assay of IL-4-producing CD3+CD4+T cells in the mediastinal lymph node (MLN) from the above disposed mice. (d) Gating strategy for flow assay of IL-17A-producing and IFN-γ-producing CD4+T cells in the MLN of the above disposed mice.

(a and b) T cell counts in lungs of KI mice, which were intravenously injected with 200 μg anti-CD4 or control IgG per mouse at 24 hours before challenge and assayed at day 6 after single intratracheal exposure to Af conidia (1×107). (c and d) Neutrophil (Ly6G+) and eosinophil (SiglecF+) counts in lungs of the above disposed mice. *P < 0.05, **P < 0.01 and ***P < 0.001. By one-way ANOVA and post hoc Tukey test. Data shown are representative of three independent experiments.